During embryonic development, sensory neurons in dorsal root ganglia (DRGs) establish connections with central and peripheral targets quite precisely, which is essential for proper sensory function. DRG axons take characteristic routes to the periphery, where they innervate skin and muscle; central connections are established later. The overall goal of this project is to elucidate the mechanisms and molecules responsible for (1) directing the long-distance growth of sensory axons to targets in the limb and central nervous system and (2) regulating the distribution of cutaneous axons within skin. Innervation patterns mapped in embryonic chicks after experimental manipulations in ovo (Wang & Scott, 1998) suggest that sensory neurons have less robust pathfinding capabilities than motoneurons and are less rigidly specified. Aim I uses similar methods to investigate (a) whether there are differences in the pathfinding capabilities of thoracic and lumbosacral DRG neurons and (b) whether DRG neurons, like motoneurons, observe a waiting period period to invading the limb. In addition, Aim I uses in situ hybridization and in ovo perturbations to investigate whether ephrins and Eph receptors are involved in sensory axon pathfinding. In Aim II, central projections of DRGs that innervate aberrant skin regions following experimental manipulations will be mapped to learn whether central projections of cutaneous neurons, like those of muscle afferents, are determine by their peripheral targets. By assessing the pathfinding capabilities of sensory neurons, Aims I and II will provide valuable information about the extent to which sensory neurons are specific prior to axon outgrowth and the types of molecular cues that guide sensory axon growth. Once outgrowing sensory axons reach the skin, which is the largest sensory organ in the body, they ramify in a characteristic fashion. For example, in birds cutaneous innervation is restricted to the dermis, with few axons penetrating the epidermis. Aim III examines the role of two important classes of molecules, chondroitin sulfate proteoglycans and neurotrophins, in regulating the distribution of axons in skin in vivo and in several in vitro model systems. The increases understanding of the mechanisms and molecules responsible for the development of sensory innervation patterns that will be obtained here is of both developmental and clinical significance. This information will provide a framework for the design and implementation of clinical strategies to promote the extend and specificity of regeneration of injured or diseased sensory axons.